Marco Meglio

People living in rural areas have long had difficulty accessing health care, a situation usually attributed to a lack of nearby care providers. But a 

 suggests the problem also lies in the financial, cultural and interpersonal challenges many rural residents face when they seek care, especially for chronic conditions. 

A team of researchers reviewed 62 studies involving more than 1,350 patients with cancer, behavioral health problems, HIV/AIDS and diabetes living in rural areas. Their goal was to study and synthesize the patients’ experiences when it came to accessing health care services.

The authors found four major “analytic themes,” and accompanying challenges, associated with the patients’ attempts to obtain care for their chronic conditions. They identified these as:

 This category included challenges such as the need to travel long distances for routine health care services while experiencing poor health, having to to rely on spouses and other caregivers for transportation, and the belief that the care available nearby was worse than that in more-distant locations.

 Problems in this category included delays in getting care due to limited availability of specific clinicians, barriers to maintaining a continuous relationship with specific doctors or organizations, inadequate communication between different providers, and frustration with inflexible scheduling and long in-clinic wait times—often followed by what they felt was inadequate time with their clinician.

 In half of the studies analyzed, patients said that living in a remote area meant they had to bear costs of transportation, overnight lodging and childcare to obtain needed care. Many patients also cited low pay and overall economic hardship in their communities as challenges in financing their care.

 While many participants said they liked living in a close-knit community with high levels of social support, they also cited the accompanying lack of privacy as a barrier to obtaining health care, especially for stigmatized conditions such as AIDS or mental health. Others complained of a lack of cultural sensitivity and stereotyping of rural residents among health care professionals and clinic support staff. Native Americans in particular, the authors say, “characterized western practitioners as paternalistic, condescending, and openly skeptical of tribal healing practices.”

The authors note that despite the overall growth of telehealth during the COVID-19 pandemic, it has been used less for patients in rural settings compared with those in urban areas. They recommend that future researchers explore how telehealth services affect the experience of care access for rural patients with chronic health conditions.

The study, “Rural Patient Experiences of Accessing Care for Chronic Conditions: A Systematic Review and Thematic Synthesis of Qualitative Studies” appears in the May 2022 issue of 

Originally published on our sister brand, 

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Study finds financial, cultural barriers to care common among rural residents.

Rural health care challenges go beyond a lack of doctors

In an effort to understand patient-valued outcome measures for headache preventive treatments, new results from a pilot study showed that adolescents care most about outcomes reflecting headache intensity, while the parents of these adolescents value outcomes directed at assessing functional impact.

The pilot study, led by Cynthia Morris, MD, pediatric neurologist, St. Louis University, included 55 adolescents with an 

International Classification of Headache Disorders

 diagnosis of chronic migraine (CM) who had continuous headache and who were being care for at a tertiary pediatric headache clinic, and 60 of their parents. Developed in Research Electronic Data Capture, the final distributed survey questionnaire contained 78 multiple-choice questions covering demographics, headache history, number of previous preventive medication treatment trials, school attendance, and questions on participant’s preferences for measuring treatment outcomes.

Although children and adolescents with CM who have continuous headache may have high levels of headache-related disability, they have been largely excluded from clinical trials. The mean age of the adolescents in this study was 16 years, 82% of whom were female. Among parents, 57% (33 of 58) reported having a history of headaches themselves. Adolescents reported a median of 24 months (IQR, 12-39) of continuous headache and parents reported a median duration of 30 months (IQR, 12-42).

Although adolescents reported a median of 2 prior preventive medication trials (IQR, 0-5), only 13% of them believed their preventive medication was helpful. Regarding functional impact of headaches, adolescents and parents reported missing a median of 10 days of activities per month. Furthermore, adolescents reported missing a median of 3 full days and 0 partial days of school per month, while parents reported a median of 4 full days and 2 partial days of school per month.

When assessing patient-valued outcome measures, headache severity was the most important category for adolescents, while parents valued functional impact of headaches, followed closely by headache frequency and severity. When asked to select the outcome measure most important to them in assessing response to headache treatment, both adolescents and parents selected frequency of severe headaches followed by intensity of background headache. Overall, outcome measures related to characteristics of the headaches themselves—frequency and intensity of headaches—were more highly ranked than those related to functional impact, associated symptoms, or acute medication use.

Morris et al noted that while these findings serve as groundwork for clinicians, "future research is encouraged to build on this work in a broader population with validated surveys that incorporate NIH common data elements and validated instruments such as PedMIDAS for assessing disability, as well as evaluation of specific headache features (eg, length of continuous headache to date) as potential moderators of patient preferences."

Within the respective categories of headache frequency and severity, 61% and 70% of adolescents reported that it was more important to measure both the frequency and intensity of severe headaches rather than the frequency or intensity of background headaches, while parents were more divided. Among outcomes reflecting need for acute intervention, both parents and adolescents felt that improved efficacy of acute medications were more important than decrease in frequency of acute medication use. In total, 75% of parents felt that decrease in frequency of contacting providers was more meaningful than decrease in frequency of emergency room visits (26%), while adolescents valued these measures equally.

The mental or cognitive impact of headaches was rated as the most important outcome by both adolescents and parents when evaluating specific outcomes related to functional impact of headache. The next highest rated outcome in this section was physical impact of headache for adolescents and emotional impact of headache for parents. Among outcomes related to associated symptoms, brain fog was reported as the most important outcome measure by both adolescents and parents.

With regard to how adolescents and parents viewed brain fog, the investigators wrote that “this measure likely reflects the significant cognitive burden continuous headache due to chronic migraine causes in this population, as reflected by evidence that higher frequency of headaches is associated with poorer school performance."


Morris C, Ross A, Greene K, Irwin S, Wagstaff A, Gelfand A. Outcomes that matter to adolescents with continuous headache due to chronic migraine and their parents: a pilot survey study. 

. Published online April 13, 2022. doi:10.1212/WNL.0000000000200292

More than 60% of adolescents felt that it was more important to measure decreases in the frequency and intensity of headaches in terms of severe headaches/spikes rather than total headache days.

Pilot study highlights outcome preferences for adolescents with chronic migraine, their parents

The FDA has approved an expanded indication for risdiplam (Evrysdi; Genentech) to include the treatment of presymptomatic babies under 2 months old with spinal muscular atrophy (SMA), making it the first approved treatment administered at home for this patient group. Risdiplam is now approved to treat SMA in both children and adults of all ages.

The decision to expand risdiplam’s indication was based off interim efficacy and safety data from the RAINBOWFISH study (NCT03779334), which showed that, following 12 months of treatment with risdiplam, a majority of presymptomatic babies met key milestones of healthy babies. This included sitting, standing, and walking, in addition to maintaining the ability to swallow.

"The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” principal investigator Richard Finkel, MD, director, Experimental Neuroscience Program, St. Jude Children’s Research Hospital, said in a statement.

 "With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed."

Risdiplam, a survival motor neuron splicing modifier, also had supportive data from the open-label extension FIREFISH study (NCT02913482) in its application. In a cohort of 58 infants aged 1 to 7 months, 91% were alive after 3 years of treatment with risdiplam. Among the 48 infants who had an available motor assessment, 32 infants maintained and 4 gained the ability to sit without support for at least 5 seconds since month 24, as assessed by the Gross Motor Scale of the Bayley Scores of Infant and Toddler Development.

"The priority review and subsequent approval of Evrysdi for babies under 2 months of age speaks to the urgent ongoing need for additional treatment options for babies with SMA,” Levi Garroway, MD, PhD, chief medical officer, and head, Global Product Development, Genentech, said in a statement.1 “Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA from presymptomatic newborns to older adults. We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers."

Among the several ongoing trials of risdiplam, FIREFISH is unique in its 2-part design. Part 1 was a dose-escalation study in 21 infants with the primary end point assessing safety and determining the dosing for Part 2. In the single-arm Part 2, 41 infants with type 1 SMA were treated for 2 years, followed by an open-label extension. Original 2-year data from Part 2 were 

, pooled participants treated with the agent for a minimum of 3 years. At the conclusion of the analysis, 20 infants maintained and 15 gained the ability to sit without support for at least 30 seconds. No infant who gained the ability to sit without support lost this ability after 3 years, and the majority of infants also maintained the ability to feed orally and swallow up to that time point.

Most infants showed the ability to improve or maintain measures on the Hammersmith Infant Neurological Examination between 24 and 36 months. This included being able to hold their heads upright (36 maintained, 3 gained, and none lost the ability since month 24), pivot while sitting (15 maintained, 11 gained, and none lost the ability), stand with support (6 maintained, 5 gained, and 1 lost the ability), and walk while holding on (1 maintained, 2 gained, and none lost the ability).

1. FDA approves Genentech’s Evrysdi (risdiplam) for use in babies under two months with spinal muscular atrophy (SMA). News release. Genentech. May 31, 2022. Accessed May 31, 2022. https://www.biospace.com/article/releases/fda-approves-genentech-s-evrysdi-risdiplam-for-use-in-babies-under-two-months-with-spinal-muscular-atrophy-sma-/?s=85

2. Roche presents new data at World Muscle Society (WMS) 2021 highlighting new advances for people living with rare neuromuscular disorders. News release. Roche. September 24, 2021. Accessed May 31, 2022. https://www.roche.com/media/releases/med-cor-2021-09-24.htm

3. New three-year data for Genentech’s Evrysdi (risdiplam) show long-term improvements in survival and motor milestones in babies with type 1 spinal muscular atrophy. News release. Genentech. April 28, 2022. Accessed May 31, 2022. https://www.gene.com/media/press-releases/14950/2022-04-28/new-three-year-data-for-genentechs-evrys

Data from the RAINBOWFISH study and a large-scale extension, FIREFISH, were the basis for risdiplam’s expanded indication, which now includes babies with SMA under 2 months old.

FDA approves risdiplam to treat presymptomatic babies under 2 months with SMA

Findings from the prospective Norwegian Mother and Child Cohort Study (MoBA) showed that among women with epilepsy on an antiseizure medication (ASM), periconceptional folic acid supplementation was associated with a lower risk of preterm birth. All told, there was a 3-fold increase in the risk among those who did not undergo supplementation vs those who did.

To evaluate whether folic acid supplementation was associated with primary outcomes such as preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia, investigators evaluated 100,105 singleton pregnancies from 1999-2008. In 764 of these pregnancies, the mother had a diagnosis of epilepsy; 316 mothers were exposed to ASM during pregnancy and 358 were not.

Folate has been shown to be essential for DNA synthesis, and the demand for folate increases during pregnancy due to uterine, placental, and fetal growth, the investigators noted. Led by Silje Alvestad, MD, PhD, postdoctoral fellow, University of Bergen, group defined the main exposure of periconceptional folic acid supplementation as intake between 4 weeks before pregnancy and 12 weeks into pregnancy.

Among those with epilepsy on an ASM, the mean gestational age at birth was 279 days (SD, 11.8) in pregnancies with periconceptional folic acid supplementation, compared with 272 days (SD, 19.8) for those without periconceptional folic acid (

 <.001). In contrast, the mean gestational age at birth was similar in those with epilepsy without ASM and those without epilepsy, regardless of folic acid supplementation.

"Our study supports the recommendation that ASM-treated women with epilepsy with a potential to become pregnancy should use daily folic acid supplement," Alvestad et al wrote. "The optimal dose of folic acid remains unknown and likely varies between ASMs and between individual women. A broad scope of studies on even larger populations are essential to assess the risks and benefits of folic acid for individual ASMs, also taking genetic variations in folate metabolism into account."

In total, 5% of the pregnancies among those with epilepsy with an ASM resulted in preterm birth for the mothers who had used folic acid supplementation periconceptionally, compared with 14% when they had not (adjusted odds ratio [aOR], 3.3; 95% CI, 1.2-9.2). Similar to previous findings, those with epilepsy not on an ASM and those without epilepsy did not demonstrate any association between folic acid supplementation and preterm birth.

Folic acid supplementation did not influence the risk of SGA. In comparison, 14% of the women without periconceptional folic acid developed SGA compared with 9% on the study treatment (aOR, 1.3; 95% CI, 0.5-3.6). For those with epilepsy who did not receive ASM, the risk of SGA was the same with (7%) and without (7%) periconceptional folic acid (aOR, 0.9; 95% CI, 0.4-2.5). Similar to SGA, there was no association between periconceptional folic acid supplement and the risk of preeclampsia, neither in women with epilepsy using ASM, not using ASM, nor in the group without epilepsy.

For ASM-treated women who used folic acid supplementation periconceptionally, the risk of preterm birth did not differ regardless of the presence of epilepsy (aOR, 0.9; 95% CI, 0.5-1.6). In contrast, ASM-treated women who did not start the supplementation until the second or third trimester had an increased risk of preterm birth compared with women without epilepsy (aOR, 2.6; 95% CI, 1.1-6.5). Notably, an even higher risk of preterm birth was observed for ASM-treated women who did not take folic acid supplement at all during pregnancy (n = 16) compared with women without epilepsy who did not take folic acid (aOR, 9.4; 95% CI, 2.6-34.8).

The use of ASMs have been shown to not have an impact on the neurodevelopment of children, according to findings from the critical MODEAD study (NCT01730170). Overall, that study found no significant differences between children of women with epilepsy vs healthy women for the primary language domain outcome on the Bayley Scales of Infant and Toddler Development, Third Edition. In the full model, significant factors such as higher maternal IQ (0.3 [95% CI, 0.1-0.4]), birth weight (3.0 [95% CI, 0.3-5.6]) and female child sex (6.4 [95% CI, 3.3-9.4]) were associated with higher language domain scores.

Alvestad S, Husebye ES, Christensen J, et al. Folic acid and risk of preterm birth, preeclampsia and fetal growth restriction among women with epilepsy: a prospective cohort study. 

 Published May 16, 2022. doi:10.1212/WNL.0000000000200669

Meador J, Cohen MJ, Loring DW, et al. 2-year-old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study. 

published online June 7, 2021. doi: 10.1001/jamaneurol.2021.1583

In total, 14% of those on antiseizure medication who did not receive periconceptional folic acid experienced preterm birth compared with 5% of those with supplementation.

Periconceptional Folic Acid Supplementation Decreases Risk of Preterm Birth in Epilepsy

The RESPONSE clinical trial (NCT04839601), a prospective single-arm study evaluating the safety and efficacy of NeuroPace’s Responsive Neurostimulation (RNS) System in adolescents aged 12 through 17 years with drug-resistant focal epilepsy, has commenced dosing.

According to clinicaltrials.gov, the study is expected to enroll 200 participants who will be followed for 2 years after placement of the RNS System. The primary outcome measure includes short-term serious adverse device effect (SADE) rate and responder rate at 12 months post-implant. The study design includes an interim analysis which will occur after the 75th implanted patient reaches 12 months post-implant. If the study achieves its primary safety and effectiveness end point goals at the interim analysis, the study will be considered successful and enrollment will be stopped.

Approved in 2013 for the treatment of medical refractory epilepsy, the RNS System remains the only brain-responsive neuromodulation system approved by the FDA. The closed-loop technology monitors and responds to a patient’s unique brain patterns to deliver therapy in real time prior to symptom onset.

"More than 1 million people are living with drug-resistant epilepsy," 

, pediatric neurologist and director, pediatric epilepsy program, Boston Children’s Health Physicians; and Patricia McGoldrick, NP, MPA, MSN, nurse practitioner and director, Pediatric Epilepsy Unit, Boston Children’s Health Physicians, said in a statement.

 “The RNS System has demonstrated unprecedented seizure reduction and improved quality of life in adults with drug-resistant focal epilepsy. Through this clinical study, we are looking forward to evaluating the RNS System in an expanded population of adolescent patients who have uncontrolled focal seizures, despite taking medications."

Since its approval, the modality has been studied in several different settings, 

including 2 seminal studies published in 2020

. The first study, which included 150 patients with refractory epilepsy, showed median seizure reductions of 67% (IQR, 33-99) at 1 year, 75% (IQR, 50-94) at 2 years, 82% (IQR, 50-96) at 3 years or more, and 74% (IQR, 50-96) at last follow-up (mean, 2.3 years). Notably, 35% of patients treated with the device had at least a 90% reduction in seizure frequency, with 18% of patients reportedly seizure-free at last follow-up.

The second trial was a 9-year, long-term study that included 230 patients across 34 epilepsy centers with nearly 1900 patient-implant years of follow-up. At 9 years, the median percent reduction in seizure frequency was 75% (

 <.0001; Wilcoxon signed rank), the responder rate was 73%, and 35% had at least a 90% reduction in seizure frequency. Additionally, 18.4% of the cohort experienced at least 1 year of seizure freedom, with 62% of those seizure-free at the last follow-up.

"The RESPONSE study is an exciting opportunity to evaluate the safety and effectiveness of the RNS System in a younger population aged 12 through 17 [years], when seizures can profoundly impact school, social development, and self-esteem, as well as expose the teen to all of the risks of seizures themselves," 

, chief medical officer, NeuroPace, and primary investigator of RESPONSE, said in a statement.

 "Our recent announcement of nearly 11 yearsof battery life for the RNS System is especially beneficial to younger patients—fewer replacement procedures translates into lower health risk and lower cost for patients."

RESPONSE is one of the many ongoing studies further evaluating the efficacy and safety of the RNS System. In July 2021, the National Institutes of Health granted an investigational device exemption (IDE) to study the modulation device in 

 Months later, in November 2021, the company received another IDE to evaluate the RNS System in patients with 

 Dubbed NAUTILUS, that prospective, randomized pivotal study is the first to evaluate the effects of brain-responsive neuromodulation in this patient population.

NeuroPace announces first patient treated in pivotal study evaluating the RNS system in adolescents. News release. NeuroPace. May 4, 2022. Accessed May 10, 2022. https://www.neuropace.com/neuropace-announces-first-patient-treated-in-pivotal-study-evaluating-the-rns-system-in-adolescents/

RNS System RESPONSE Study (RESPONSE). Clinicaltrial.gov. https://clinicaltrials.gov/ct2/show/NCT04839601. Updated April 14, 2022. Accessed May 10, 2022.

Razavi B, Rao VR, Lin C, et al. Real-world experience with direct brain-responsive neurostimulation for focal onset seizures. 

 2020;61(8):1749-1757. doi:10.1111/epi.16593.Epub 2020. Jul 13.

Nair DR, Laxer KD, Weber PB. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. 

 2020;95(9)e1244-e1256. doi:10.1212/WNL.0000000000010154

NeuroPace awarded five-year NIH grant funding of more than $9M to study RNS system in Patients with Lennox-Gastaut Syndrome. News release. NeuroPace, Inc. June 30, 2021. Accessed May 10, 2022. https://www.globenewswire.com/news-release/2021/06/30/2255588/0/en/NeuroPace-Awarded-Five-Year-NIH-GraThent-Funding-of-More-than-9M-to-Study-RNS-System-in-Patients-with-Lennox-Gastaut-Syndrome.html

NeuroPace receives IDE approval to initiate NAUTILUS pivotal study of its RNS System for idiopathic generalized epilepsy. News release. November 10, 2021. Accessed May 10 2022. https://www.globenewswire.com/news-release/2021/11/10/2331968/0/en/NeuroPace-Receives-IDE-Approval-to-Initiate-NAUTILUS-Pivotal-Study-of-its-RNS-System-for-Idiopathic-Generalized-Epilepsy.html